Fetal alveolar type II (fATII) epithelial cells were used to evaluate the role of signaling factors involved in oxidative stress-induced programmed cell death (PCD; apoptosis). Bcl-2, an antiapoptotic proto-oncogene, showed maximum abundance in hypoxia and mild reoxygenation, but declined thereafter. The Bcl-2 counterpart, Bax, which promotes PCD, displayed an increasing log arithmic profile with ascending ΔpO2 regimen, such that the ratio of Bcl-2/Bax decreased as pO2 increased. The expression of p53, a cell cycle regulator, paralleled Bax abundance. Pretreatment of fATII cells with L-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), enhanced Bax and p53 expression over Bcl-2. The GSH analogue, γ-glutamylcysteinyl-ethyl ester, down-regulated Bax/p53 abundance but restored that of Bcl-2, thereby increasing Bcl-2/Bax. The antioxidant and GSH precursor N-acetyl-L-cysteine favored Bcl-2 at the expense of Bax/p53, whereas pyrrolidine dithiocarbamate induced Bax against Bcl-2, with mild effect on p53. Sulfasalazine, a potent and specific inhibitor of NF-κB, induced Bax at the expense of Bcl-2, in a p53-dependent manner. We conclude that the differential expression of signaling factors involved in PCD in the alveolar epithelium is redox-sensitive and mediated, at least in part, by a negative feedback mechanism transduced by NF-κB. (C) 2000 Academic Press.
|Number of pages||11|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 29 Apr 2000|
- NF-κB (RelA/p65)
- Pyrrolidine dithiocarbamate
- Redox equilibrium